Anti-rheumatoid arthritis effects of traditional Chinese medicine Fufang Xiaohuoluo pill on collagen-induced arthritis rats and MH7A cells.

Background: Fufang Xiaohuoluo pill (FFXHL) is a commonly used prescription in clinical practice for treating rheumatoid arthritis in China, yet its specific mechanism remains unclear. This study aims to elucidate the pharmacological mechanisms of FFXHL using both in vivo and in vitro experiments. Methods: The collagen-induced arthritis (CIA) rat model was established to evaluate FFXHL's therapeutic impact. Parameters that include paw swelling, arthritis scores, and inflammatory markers were examined to assess the anti-inflammatory and analgesic effects of FFXHL. Human fibroblast-like synoviocytes (MH7A cells) is activated by tumour necrosis factor-alpha (TNF-α) were used to explore the anti-inflammatory mechanism on FFXHL. Results: Our findings indicate that FFXHL effectively reduced paw swelling, joint pain, arthritis scores, and synovial pannus hyperplasia. It also lowered serum levels of TNF-α, interleukin-1ß (IL1ß), and interleukin-6 (IL-6). Immunohistochemical analysis revealed decreased expression of nuclear factor-kappa B (NF-κB) p65 in FFXHL-treated CIA rat joints. In vitro experiments demonstrated FFXHL's ability to decrease protein secretion of IL-1ß and IL-6, suppress mRNA expression of matrix metalloproteinases (MMP) -3, -9, and -13, reduce reactive oxygen species (ROS) levels, and inhibit NF-κB p65 translocation in TNF-α stimulated MH7A cells. FFXHL also suppressed protein levels of extracellular signal-regulated kinase (ERK), c-Jun Nterminal kinase (JNK), p38 MAP kinase (p38), protein kinase B (Akt), p65, inhibitor of kappa B kinase α/ß (IKKα/ß), Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) induced by TNF-α in MH7A cells. Conclusion: The findings imply that FFXHL exhibits significant anti-inflammatory and antiarthritic effects in both CIA rat models and TNF-α-induced MH7A cells. The potential mechanism involves the inactivation of TLR4/MyD88, mitogen-activated protein kinases (MAPKs), NF-κB, and Akt pathways by FFXHL.

An efficient Fusion-Purification Network for Cervical pap-smear image classification.

BACKGROUND AND OBJECTIVES: In cervical cell diagnostics, autonomous screening technology constitutes the foundation of automated diagnostic systems. Currently, numerous deep learning-based classification techniques have been successfully implemented in the analysis of cervical cell images, yielding favorable outcomes. Nevertheless, efficient discrimination of cervical cells continues to be challenging due to large intra-class and small inter-class variations. The key to dealing with this problem is to capture localized informative differences from cervical cell images and to represent discriminative features efficiently. Existing methods neglect the importance of global morphological information, resulting in inadequate feature representation capability. METHODS: To address this limitation, we propose a novel cervical cell classification model that focuses on purified fusion information. Specifically, we first integrate the detailed texture information and morphological structure features, named cervical pathology information fusion. Second, in order to enhance the discrimination of cervical cell features and address the data redundancy and bias inherent after fusion, we design a cervical purification bottleneck module. This model strikes a balance between leveraging purified features and facilitating high-efficiency discrimination. Furthermore, we intend to unveil a more intricate cervical cell dataset: Cervical Cytopathology Image Dataset (CCID). RESULTS: Extensive experiments on two real-world datasets show that our proposed model outperforms state-of-the-art cervical cell classification models. CONCLUSIONS: The results show that our method can well help pathologists to accurately evaluate cervical smears.

An oleanic acid decorated gold nanorod for highly efficient inhibition of hemagglutinin and visible rapid detection of the influenza virus.

Accurate diagnosis and effective antiviral treatments are urgently needed for the prevention and control of flu caused by influenza viruses. In this study, a novel oleanic acid (OA) functionalized gold nanorod OA-AuNP was prepared through a convenient ligand-exchange reaction. As hemagglutinin (HA) on the viral surface binds strongly to the multiple OA molecules on the surface of the nanoparticle, the prepared OA-AuNP was found to exhibit potent antiviral activity against a wide range of influenza A virus strains. Furthermore, the change in color resulting from the specific binding between HA and OA and the resultant aggregation of the OA-AuNP can be visually observed or measured by UV-vis spectra with a detection limit of 2 and 0.18 hemagglutination units (HAU), respectively, which is comparable to the commercially available influenza colloid gold rapid diagnostic kits. These findings demonstrate the potential of the OA-AuNP for the development of novel multivalent antiviral conjugates and the diagnosis of influenza virus.

Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury.

Background: Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Methods: Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. Results: The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFß signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-associated ARDS is stronger compared to sepsis-related ARDS. In sepsis-related ARDS, CD8+ T and Th cells exhibit more prominent signaling to B-cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-related ARDS. Conclusion: This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.

Seed pretreatment with brassinosteroids stimulates sunflower immunity against parasitic weed (Orobanche cumana) infection.

Broomrape (Orobanche cumana) negatively affects sunflower, causing severe yield losses, and thus, there is a need to control O. cumana infestation. Brassinosteroids (BRs) play key roles in plant growth and provide resilience to weed infection. This study aims to evaluate the mechanisms by which BRs ameliorate O. cumana infection in sunflower (Helianthus annuus). Seeds were pretreated with BRs (1, 10, and 100 nM) and O. cumana inoculation for 4 weeks under soil conditions. O. cumana infection significantly reduced plant growth traits, photosynthesis, endogenous BRs and regulated the plant defence (POX, GST), BRs signalling (BAK1, BSK1 to BSK4) and synthesis (BRI1, BR6OX2) genes. O. cumana also elevated the levels of malondialdehyde (MDA), hydroxyl radical (OH-), hydrogen peroxide (H2O2) and superoxide (O2 •-) in leaves/roots by 77/112, 63/103, 56/97 and 54/89%, as well as caused ultrastructural cellular damages in both leaves and roots. In response, plants activated a few enzymes, superoxide dismutase (SOD), peroxidase (POD) and reduced glutathione but were unable to stimulate the activity of ascorbate peroxidase (APX) and catalase (CAT) enzymes. The addition of BRs (especially at 10 nM) notably recovered the ultrastructural cellular damages, lowered the production of oxidative stress, activated the key enzymatic antioxidants and induced the phenolic and lignin contents. The downregulation in the particular genes by BRs is attributed to the increased resilience of sunflower via a susceptible reaction. In a nutshell, BRs notably enhanced the sunflower resistance to O. cumana infection by escalating the plant immunity responses, inducing systemic acquired resistance, reducing oxidative or cellular damages, and modulating the expression of BR synthesis or signalling genes.

The prognostic and immunological role of MCM3 in pan-cancer and validation of prognosis in a clinical lower-grade glioma cohort.

Background: Previous studies have shown that MCM3 plays a key role in initiating DNA replication. However, the mechanism of MCM3 function in most cancers is still unknown. The aim of our study was to explore the expression, prognostic role, and immunological characteristics of MCM3 across cancers. Methods: We explored the expression pattern of MCM3 across cancers. We subsequently explored the prognostic value of MCM3 expression by using univariate Cox regression analysis. Spearman correlation analysis was performed to determine the correlations between MCM3 and immune-related characteristics, mismatching repair (MMR) signatures, RNA modulator genes, cancer stemness, programmed cell death (PCD) gene expression, tumour mutation burden (TMB), microsatellite instability (MSI), and neoantigen levels. The role of MCM3 in predicting the response to immune checkpoint blockade (ICB) therapy was further evaluated in four immunotherapy cohorts. Single-cell data from CancerSEA were analysed to assess the biological functions associated with MCM3 in 14 cancers. The clinical correlation and independent prognostic significance of MCM3 were further analysed in the TCGA and CGGA lower-grade glioma (LGG) cohorts, and a prognostic nomogram was constructed. Immunohistochemistry in a clinical cohort was utilized to validate the prognostic utility of MCM3 expression in LGG. Results: MCM3 expression was upregulated in most tumours and strongly associated with patient outcomes in many cancers. Correlation analyses demonstrated that MCM3 expression was closely linked to immune cell infiltration, immune checkpoints, MMR genes, RNA modulator genes, cancer stemness, PCD genes and the TMB in most tumours. There was an obvious difference in outcomes between patients with high MCM3 expression and those with low MCM3 expression in the 4 ICB treatment cohorts. Single-cell analysis indicated that MCM3 was mainly linked to the cell cycle, DNA damage and DNA repair. The expression of MCM3 was associated with the clinical features of LGG patients and was an independent prognostic indicator. Finally, the prognostic significance of MCM3 in LGG was validated in a clinical cohort. Conclusion: Our study suggested that MCM3 can be used as a potential prognostic marker for cancers and may be associated with tumour immunity. In addition, MCM3 is a promising predictor of immunotherapy responses.

The role of exposure condition, awareness and item type in developing implicit and explicit knowledge of collocational rules.

This study expands on previous SLA research by focusing on learning collocational rules. The study also explores the interaction between exposure conditions, awareness, and item-related variables in the context of collocation learning. Chinese learners of English were exposed to sentences from large corpora, featuring four target node verbs (replaced with pseudowords) and their respective noun collocates. There are two pairs of novel verbs with different L1-L2 congruencies in the experimental material. Participants were divided into incidental and intentional groups. The learning effectiveness was assessed through a plausibility judgment test (PJT), which included trained, new, and swapped items. Awareness of the underlying rules was measured using source attributions, retrospective verbal reports, and posttest thinking aloud. The results revealed that participants acquired both explicit and implicit knowledge of collocational rules. Rule-searching led to greater explicit knowledge but did not improve overall learning outcomes. Additionally, an interaction was observed among awareness, rule type, and test type. As the difficulty level increased in terms of L1-L2 congruency or item type, the importance of awareness in meeting the learning demands also increased.

The effects of IL-27 and IL-35 gene variation and expression levels on the susceptibility and clinical manifestations of pulmonary tuberculosis.

Inflammatory cytokines have crucial roles in the pathogenesis of tuberculosis (TB), and interleukin (IL)-27 and IL-35 have a pro-inflammatory and anti-inflammatory effect on many diseases, including infectious diseases. Therefore, we evaluated the relationship between IL-27 and IL-35 gene polymorphism, expression levels, and pulmonary TB (PTB) susceptibility. Nine single-nucleotide polymorphisms (SNPs) in the IL-27 gene (rs181206, rs153109, and rs17855750) and the IL-35 gene (rs4740, rs428253, rs9807813, rs2243123, rs2243135, and rs568408) were genotyped by the SNPscan technique in 497 patients with PTB and 501 controls. There was no significant difference regarding the genotype and allele frequencies of the above SNPs in the IL-27 and IL-35 genes between patients with PTB and controls. Haplotype analysis showed that the frequency of the GAC haplotype in the IL-35 gene was significantly decreased in patients with PTB when compared to controls (p = 0.036). Stratified analysis suggested that the frequency of the IL-27 rs17855750 GG genotype was significantly increased in patients with PTB with fever. Moreover, the lower frequency of the IL-35 rs568408 GA genotype was associated with drug-induced liver injury in patients with PTB. The IL-35 rs428253 GC genotype, as well as the rs4740 AA genotype and A allele, showed significant relationships with hypoproteinemia in patients with PTB. When compared with controls, the IL-27 level was significantly increased in patients with PTB. Taken together, IL-35 gene variation might contribute to a protective role on the susceptibility to PTB, and IL-27 and IL-35 gene polymorphisms were associated with several clinical manifestations of patients with PTB.

Magnitude and determinants of excess total, age-specific and sex-specific all-cause mortality in 24 countries worldwide during 2020 and 2021: results on the impact of the COVID-19 pandemic from the C-MOR project.

INTRODUCTION: To examine the impact of the COVID-19 pandemic on mortality, we estimated excess all-cause mortality in 24 countries for 2020 and 2021, overall and stratified by sex and age. METHODS: Total, age-specific and sex-specific weekly all-cause mortality was collected for 2015-2021 and excess mortality for 2020 and 2021 was calculated by comparing weekly 2020 and 2021 age-standardised mortality rates against expected mortality, estimated based on historical data (2015-2019), accounting for seasonality, and long-term and short-term trends. Age-specific weekly excess mortality was similarly calculated using crude mortality rates. The association of country and pandemic-related variables with excess mortality was investigated using simple and multilevel regression models. RESULTS: Excess cumulative mortality for both 2020 and 2021 was found in Austria, Brazil, Belgium, Cyprus, England and Wales, Estonia, France, Georgia, Greece, Israel, Italy, Kazakhstan, Mauritius, Northern Ireland, Norway, Peru, Poland, Slovenia, Spain, Sweden, Ukraine, and the USA. Australia and Denmark experienced excess mortality only in 2021. Mauritius demonstrated a statistically significant decrease in all-cause mortality during both years. Weekly incidence of COVID-19 was significantly positively associated with excess mortality for both years, but the positive association was attenuated in 2021 as percentage of the population fully vaccinated increased. Stringency index of control measures was positively and negatively associated with excess mortality in 2020 and 2021, respectively. CONCLUSION: This study provides evidence of substantial excess mortality in most countries investigated during the first 2 years of the pandemic and suggests that COVID-19 incidence, stringency of control measures and vaccination rates interacted in determining the magnitude of excess mortality.

The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer.

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial ß oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/ß-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.

Prognostic factors and predictive models for patients with lung large cell neuroendocrine carcinoma: Based on SEER database.

BACKGROUND: Lung Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive, high-grade neuroendocrine carcinoma with a poor prognosis, mainly seen in elderly men. To date, we have found no studies on predictive models for LCNEC. METHODS: We extracted data from the Surveillance, Epidemiology, and End Results (SEER) database of confirmed LCNEC from 2010 to 2018. Univariate and multivariate Cox proportional risk regression analyses were used to identify independent risk factors, and then we constructed a novel nomogram and assessed the predictive effectiveness by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: A total of 2546 patients with LCNEC were included, excluding those diagnosed with autopsy or death certificate, tumor, lymph node, metastasis (TNM) stage, tumor grade deficiency, etc., and finally, a total of 743 cases were included in the study. After univariate and multivariate analyses, we concluded that the independent risk factors were N stage, intrapulmonary metastasis, bone metastasis, brain metastasis, and surgical intervention. The results of ROC curves, calibration curves, and DCA in the training and validation groups confirmed that the nomogram could accurately predict the prognosis. CONCLUSIONS: The nomogram obtained from our study is expected to be a useful tool for personalized prognostic prediction of LCNEC patients, which may help in clinical decision-making.

Behavioral and social drivers of COVID-19 vaccination initiation in the US: a longitudinal study March─ October 2021.

Many studies have examined behavioral and social drivers of COVID-19 vaccination initiation, but few have examined these drivers longitudinally. We sought to identify the drivers of COVID-19 vaccination initiation using the Behavioral and Social Drivers of Vaccination (BeSD) Framework. Participants were a nationally-representative sample of 1,563 US adults who had not received a COVID-19 vaccine by baseline. Participants took surveys online at baseline (spring 2021) and follow-up (fall 2021). The surveys assessed variables from BeSD Framework domains (i.e., thinking and feeling, social processes, and practical issues), COVID-19 vaccination initiation, and demographics at baseline and follow-up. Between baseline and follow-up, 65% of respondents reported initiating COVID-19 vaccination. Vaccination intent increased from baseline to follow-up (p < .01). Higher vaccine confidence, more positive social norms towards vaccination, and receiving vaccine recommendations at baseline predicted subsequent COVID-19 vaccine initiation (all p < .01). Among factors assessed at follow-up, social responsibility and vaccine requirements had the greatest associations with vaccine initiation (all p < .01). Baseline vaccine confidence, social norms, and vaccination recommendations were associated with subsequent vaccine initiation, all of which could be useful targets for behavioral interventions. Furthermore, interventions that highlight social responsibility to vaccinate or promote vaccination requirements could also be beneficial.

Visual function loss in fungal sphenoid sinusitis: clinical characteristics and outcomes.

Potentially fatal fungal sphenoid sinusitis (FSS) causes visual damage. However, few studies have reported on its visual impairment and prognosis. Five hundred and eleven FSS patients with ocular complications treated at Beijing Tongren Hospital were recruited and clinical features and visual outcomes were determined. Thirty-two of the 511 patients (6%) had visual impairment, with 13 and 19 patients having invasive and noninvasive FSS, respectively. Eighteen patients (56.25%) had diabetes and 2 patient (6.25%) had long-term systemic use of antibiotics (n = 1) and corticosteroids (n = 1). All patients had visual impairment, which was more severe in invasive FSS than in noninvasive FSS. Bony wall defects and sclerosis were observed in 19 patients (59.38%), and 11 patients (34.38%) had microcalcification in their sphenoid sinusitis on computed tomography (CT). After a 5-year follow-up, three patients (9.38%) died. Patients with noninvasive FSS had a higher improvement rate in visual acuity than their counterparts. In the multivariate analysis, sphenoid sinus wall sclerosis on CT was associated with better visual prognosis. FSS can cause vision loss with persistent headaches, particularly in those with diabetes. CT showed the sphenoid sinus wall sclerosis, indicating a better visual prognosis in FSS with visual impairment.

Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

Phenotypic high-throughput screening identifies aryl hydrocarbon receptor agonism as common inhibitor of toxin-induced retinal pigment epithelium cell death.

The retinal pigment epithelium (RPE) is essential to maintain retinal function, and RPE cell death represents a key pathogenic stage in the progression of several blinding ocular diseases, including age-related macular degeneration (AMD). To identify pathways and compounds able to prevent RPE cell death, we developed a phenotypic screening pipeline utilizing a compound library and high-throughput screening compatible assays on the human RPE cell line, ARPE-19, in response to different disease relevant cytotoxic stimuli. We show that the metabolic by-product of the visual cycle all-trans-retinal (atRAL) induces RPE apoptosis, while the lipid peroxidation by-product 4-hydroxynonenal (4-HNE) promotes necrotic cell death. Using these distinct stimuli for screening, we identified agonists of the aryl hydrocarbon receptor (AhR) as a consensus target able to prevent both atRAL mediated apoptosis and 4-HNE-induced necrotic cell death. This works serves as a framework for future studies dedicated to screening for inhibitors of cell death, as well as support for the discussion of AhR agonism in RPE pathology.

Surviving the Storm: The Role of Poly- and Depolyploidization in Tissues and Tumors.

Polyploidization and depolyploidization are critical processes in the normal development and tissue homeostasis of diploid organisms. Recent investigations have revealed that polyaneuploid cancer cells (PACCs) exploit this ploidy variation as a survival strategy against anticancer treatment and for the repopulation of tumors. Unscheduled polyploidization and chromosomal instability in PACCs enhance malignancy and treatment resistance. However, their inability to undergo mitosis causes catastrophic cellular death in most PACCs. Adaptive ploid reversal mechanisms, such as multipolar mitosis, centrosome clustering, meiosis-like division, and amitosis, counteract this lethal outcome and drive cancer relapse. The purpose of this work is to focus on PACCs induced by cytotoxic therapy, highlighting the latest discoveries in ploidy dynamics in physiological and pathological contexts. Specifically, by emphasizing the role of "poly-depolyploidization" in tumor progression, the aim is to identify novel therapeutic targets or paradigms for combating diseases associated with aberrant ploidies.

Promotion of apoplastic oxidative burst by artificially selected GhCBSX3A enhances Verticillium dahliae resistance in upland cotton.

Verticillium wilt (VW) is a devasting disease affecting various plants, including upland cotton, a crucial fiber crop. Despite its impact, the genetic basis underlying cotton's susceptibility or defense against VW remains unclear. Here, we conducted a genome-wide association study on VW phenotyping in upland cotton and identified a locus on A13 that is significantly associated with VW resistance. We then identified a cystathionine ß-synthase domain gene at A13 locus, GhCBSX3A, which was induced by Verticillium dahliae. Functional analysis, including expression silencing in cotton and overexpression in Arabidopsis thaliana, confirmed that GhCBSX3A is a causal gene at the A13 locus, enhancing SAR-RBOHs-mediated apoplastic oxidative burst. We found allelic variation on the TATA-box of GhCBSX3A promoter attenuated its expression in upland cotton, thereby weakening VW resistance. Interestingly, we discovered that altered artificial selection of GhCBSX3A_R (an elite allele for VW) under different VW pressures during domestication and other improved processes allows specific human needs to be met. Our findings underscore the importance of GhCBSX3A in response to VW, and we propose a model for defense-associated genes being selected depending on the pathogen's pressure. The identified locus and gene serve as promising targets for VW resistance enhancement in cotton through genetic engineering.

Identification of plant microRNAs using convolutional neural network.

MicroRNAs (miRNAs) are of significance in tuning and buffering gene expression. Despite abundant analysis tools that have been developed in the last two decades, plant miRNA identification from next-generation sequencing (NGS) data remains challenging. Here, we show that we can train a convolutional neural network to accurately identify plant miRNAs from NGS data. Based on our methods, we also present a user-friendly pure Java-based software package called Small RNA-related Intelligent and Convenient Analysis Tools (SRICATs). SRICATs encompasses all the necessary steps for plant miRNA analysis. Our results indicate that SRICATs outperforms currently popular software tools on the test data from five plant species. For non-commercial users, SRICATs is freely available at https://sourceforge.net/projects/sricats.

Two Randomized Controlled Trials of Nudges to Encourage Referrals to Centralized Pharmacy Services for Evidence-Based Statin Initiation in High-Risk Patients: Rationale and Design of the SUPER LIPID Program.

BACKGROUND: In patients with or at risk for atherosclerotic vascular disease, statins reduce the incidence of major adverse cardiovascular events, but the majority of U.S. adults with an indication for statin therapy are not prescribed statins at guideline-recommended intensity. Clinicians' limited time to address preventative care issues is cited as one factor contributing to gaps in statin prescribing. Centralized pharmacy services can fulfill a strategic role for population health management through outreach, education, and statin prescribing for patients at elevated ASCVD risk, but best practices for optimizing referrals of appropriate patients are unknown. STUDY DESIGN AND OBJECTIVES: SUPER LIPID (NCT05537064) is a program consisting of two pragmatic clinical trials testing the effect of nudges in increasing referrals of appropriate patients to a centralized pharmacy service for lipid management, conducted within 11 primary care practices in a large community health system. In both trials, patients were eligible for inclusion if they had an assigned primary care provider (PCP) in a participating practice and were not prescribed a high- or moderate-intensity statin despite an indication, identified via an electronic health record (EHR) algorithm. Trial #1 was a stepped wedge trial, conducted at a single practice with randomization at the PCP level, of an interruptive EHR message that appeared during eligible patients' visits and facilitated referral to the pharmacy service. For the first 3 months, no PCPs received the message; for the second 3 months, half were randomly selected to receive the message; and for the last 3 months, all PCPs received the message. Trial #2 was a cluster-randomized trial conducted at 10 practices, with randomization at the practice level. Practices were randomized to usual care or to have eligible patients automatically referred to centralized pharmacy services via a referral order placed in PCPs EHR inboxes for co-signature. In both trials, when a patient was referred to centralized pharmacy services, a pharmacist reviewed the patient's chart, contacted the patient, and initiated statin therapy if the patient agreed. The primary endpoint of both trials was the proportion of patients prescribed a statin; secondary endpoints include the proportion of patients prescribed a statin at guideline-recommended intensity, the proportion of patients filling a statin prescription, and serum low-density lipoprotein level. CONCLUSIONS: SUPER LIPID is a pair of pragmatic clinical trials assessing the effectiveness of two strategies to encourage referral of appropriate patients to a centralized pharmacy service for lipid management. The trial results will develop the evidence base for simple, scalable, EHR-based strategies to integrate clinical pharmacists into population health management and increase appropriate statin prescribing. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; NCT05537064.

Physical breakdown of CH4 hydrate under stress: a molecular dynamics simulation study.

As a solid energy source, CH4 hydrate will inevitably break down physically as the result of geological movement or exploitation. Here, the molecular dynamics method was employed to simulate the uniaxial-deformation behavior of structure I (sI type) CH4 hydrate under stress. The stress increases regardless of whether the hydrate is stretched or squeezed, and other physical parameters also changed, such as hydrate cage numbers, order parameters, and the number of water molecules. A noticeable difference is observed between the two systems. Upon stretching, the stress immediately recovers to 0 GPa once the hydrate is completely stretched apart. During the squeeze process, the stress is ultimately not zero since solid and liquid are always in contact. When the hydrate is stretched apart, about 5% of water molecules change from solid to liquid, about 7.8% of CH4 molecules lose their shelter and become free due to the disintegration of water cages. While in the squeezing process, large cages (51262) are crushed more easily than small cages (512); in the end, about 93.5% of large cages and 73% of small cages are crushed, and approximately 87.5% CH4 is released from the cages. In mining CH4 hydrates, caution must be exercised, as if the hydrates break as a result of stress, a large release of CH4 may pose a security risk.